Synthesis of non-proteinogenic amino acids using Michael addition to unsaturated orthopyroglutamate derivative

Article abstract of DOI:10.1016/j.tet.2008.10.092

Stereoselective synthesis of non-proteinogenic amino acids via Michael addition to 3,4-didehydropyroglutamate derivative in which the carboxyl function is protected as a 2,7,8-trioxabicyclo[3.2.1]octane (ABO ester) group is described. The obtained 3-subst

Full text of DOI:10.1016/j.tet.2008.10.092

Tetrahedron 65 (2009) 128–133
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Synthesis of non-proteinogenic amino acids using Michael addition to
unsaturated orthopyroglutamate derivative
*
*
Makoto Oba , Tsuneki Saegusa, Naohiro Nishiyama, Kozaburo Nishiyama
Department of Materials Chemistry, Tokai University, 317 Nishino, Numazu, Shizuoka 410-0395, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 October 2008
Received in revised form 24 October 2008
Accepted 29 October 2008
Available online 6 November 2008
Stereoselective synthesis of non-proteinogenic amino acids via Michael addition to 3,4-didehydropyro-
glutamate derivative in which the carboxyl function is protected as a 2,7,8-trioxabicyclo[3.2.1]octane
(ABO ester) group is described. The obtained 3-substituted pyroglutamic ABO ester was directly con-
verted to 3-substituted glutamic acids such as chlorpheg by acidic hydrolysis, whereas 3-substituted
proline derivatives were obtained by chemoselective reduction of the lactam carbonyl group. A formal
total synthesis of baclofen, a
g
-aminobutyric acid (GABA) analogue, is also described.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Amino acids
Pyroglutaminol
Michael addition
ABO ester
1. Introduction
group of unsaturated pyroglutamate, and demonstrated its utility as
a Michael acceptor.13
Non-proteinogenic amino acids are compounds of interest as
biologically active substrates, chiral building blocks, and compo-
nents of oligopeptides and proteins.1 For the preparation of such
We herein describe the stereoselective synthesis of some non-
proteinogenic amino acids via Michael addition to the unsaturated
ABO ester 1. As shown in Figure 1, hydrolysis of the Michael adduct
directly yields 3-substituted glutamic acids, whereas 3-substituted
prolines can be obtained by chemoselective reduction of the lactam
amino acids,
L-pyroglutamic acid is often employed as a starting
material.2,3 Among a wide variety of synthons derived from
L-
pyroglutamic acid, unsaturated pyroglutaminol derivatives are well
suited as versatile chiral templates because the olefin functionality
can be easily modified by conjugate addition, dihydroxylation,
cyclopropanation, epoxidation, cycloaddition and so on.4 However,
the procedure requires reduction of the carboxyl group in order to
perform the above transformations without affecting the integrity
of chirality. After the required modifications have been completed,
the carboxyl group must be regenerated if necessary.
carbonyl group. Construction of the 3-substituted g-aminobutyric
acid (GABA) framework is also feasible by a decarboxylation re-
action. In this work, a formal total synthesis of baclofen is
demonstrated.
2. Results and discussion
First, we examined the stereoselective introduction of sub-
Recently, we have reported the synthesis of a novel unsaturated
pyroglutamate derivative 1 in which the carboxyl function was
protected as a 5-methyl-2,7,8-trioxabicyclo[3.2.1]octane5 (ABO es-
ter).6,7 The unsaturated orthopyroglutamate 1 was found to be an
excellent substrate for the synthesis of non-proteinogenic amino
acids where redox treatment of the carboxyl group, as described
above, was unnecessary. During the course of our previous in-
vestigation, Herdeisandco-workersemployedCorey’sOBOester8–12
(4-methyl-2,6,7-trioxabicyclo[2.2.2]octane) as a carboxyl protecting
stituents at the b-position of the pyroglutamate skeleton by a Mi-
chael-type conjugate addition of nucleophiles. The results are listed
in Table 1.
Treatment of Michael acceptor 1 with a Gilman reagent, pre-
pared from MeLi and CuI, at ꢀ80 ꢁC gave methylated derivative 2a
in 90% yield (entry 1). Similar reactions with Grignard-cuprates
containing phenyl and 4-chlorophenyl groups proceeded smoothly
to produce the 1,4-adducts 2b and 2c in 71 and 68% yields, re-
spectively (entries 2 and 3). In these cuprate additions, higher
yields were obtained in comparison with the Herdeis’ work.13 The
addition of sodium diethyl malonate also afforded Michael adduct
2d in quantitative yield (entry 4).
The 1H NMR spectra of the ABO derivatives 2a–d were too
complex to be analyzed properly. In all cases, the stereochemistry
* Corresponding authors. Tel.: þ81 55 968 1111; fax: þ81 55 968 1155.
E-mail address: makoto@wing.ncc.u-tokai.ac.jp (M. Oba).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.092

M. Oba et al. / Tetrahedron 65 (2009) 128–133
129
R
HO2C
CO2H
NH2
3-substituted glutamic acid
R
hydrolysis
R
ii
O
O
(i) reduction
i
Michael addition
CO2H
N
O
O
N
N
O
H
O
Boc
Boc
O
O
3-substituted proline
1
(ii) decarboxylation
R
HO2C
3-substituted γ-aminobutyric acid (GABA)
Figure 1. Synthetic course of non-proteinogenic amino acids.
NH2
Table 1
The structure of the Michael adducts 2 was also confirmed after
converting to 3-substituted glutamic acids. A closely related work
has been reported by Herdeis and co-workers,13 where 3-
substituted glutamic acids were obtained from the corresponding
OBO ester in a three-step sequence. When a mixture of ABO ester
2a and 6 M HCl was refluxed overnight, deprotection of the Boc
group, ring opening and hydrolysis of the ABO group took place
simultaneously to produce 3-methylglutamic acid hydrochloride,
which led to a free amino acid 3a in 50% yield upon treatment with
propylene oxide. Its physical and spectral data are in accordance
with those of the reported (2S,3S)-isomer,13 suggesting exclusive
addition of the Gilman reagent towards the Michael acceptor 1 anti
to the resident ABO moiety. This result prompted us to examine
concise preparation of 3-(4-chlorophenyl)glutamic acid (chlor-
Michael addition to unsaturated orthopyroglutamate 1
R
O
O
O
nucleophile
O
O
N
N
O
Boc
Boc
O
O
1
2a-d
Entry
Reagent
Me2CuLi
R
Yielda (%)
1
2
3
4
Me (2a)
Ph (2b)
90
71
68
Quant
Ph2CuMgBr
(4-ClC6H4)2CuMgBr
NaCH(CO2Et)2
4-ClC6H4 (2c)
CH(CO2Et)2 (2d)
a
Isolated yield.
pheg),16–18 which has shown to be a selective
L-homocysteate up-
take inhibitor. As expected, chlorpheg 3c could be obtained in 63%
yield by simply refluxing the adduct 2c in 6 M HCl.
of the b-position was tentatively assigned on the basis of addition
from the less-hindered face. In order to determine the stereo-
chemical course of the addition reactions, the ABO ester was con-
verted to the corresponding methyl ester by HCl-promoted
methanolysis. Subsequent reprotection of the amido proton liber-
ated during the alcoholysis by a Boc group furnished methyl
pyroglutamate derivatives 4a–d in good yields (Scheme 1). By
comparing the observed vicinal coupling constants (J¼3–4 Hz)
Further modification of the pyroglutamate 4a–d to produce the
3-substituted proline was accomplished by chemoselective re-
duction of the lactam carbonyl group. As shown in Scheme 1,
treatment of pyroglutamate 4a with 3 equiv of borane–THF at room
temperature effected a smooth reduction, giving 3-methylprolinate
5a in 94% yield. Deprotection of 5a in refluxing 1 M HCl followed by
an ion exchange treatment with DOWEX 50WX8 resin furnished
(2S,3S)-3-methylproline 6a in 90% yield. Similar treatments of 4b
and 4c led to 3-arylprolines 6b and 6c, the conformationally re-
stricted analogues of phenylalanine and chlorpheg, respectively, in
good yields. However, exposure of 4d to borane–THF resulted in the
formation of a complex mixture. Therefore, a two-step sequencewas
adopted to reduce the lactam carbonyl moiety of 4d (Scheme 2).
between the
a
- and
b
-protons with those of related systems (J¼3.4–
3.9 Hz),14,15 the relative configuration was assigned to be trans.
R
i or ii
HO2C
CO2H
NH2
2a-d
3a
iii
EtO2C
3c (chlorpheg)
CO2Et
CO2H
CO2H
i
ii
4d
R
R
R
CO2Me
N
H
N
H
iv
v
CO2Me
CO2Me
CO2H
O
N
N
N
H
7
8 (CPAA)
Boc
Boc
Scheme 2. Preparation of (2S,3R)-2-carboxypyrrolidine-3-acetic acid (8, CPAA). Re-
agents and conditions: (i) DIBAL-H, then Et3SiH, BF3–OEt2; (ii) 1 M HCl, then DOWEX
50WX8, 53% (3 steps).
4a-d
5a-c
6a-c
a: R = Me, b: R = Ph, c: R = 4-ClC6H4,
d: R = CH(CO2Et)2
Despite the presence of five carbonyl functions in 4d, we found
that treatment with DIBAL-H followed by triethylsilane in the
presence of boron trifluoride allowed selective reduction of the
lactam carbonyl group,19,20 yielding the prolinate 7, which was then
submitted to deprotection and decarboxylation procedure to
Scheme 1. Synthesis of 3-substituted glutamic acids and prolines. Reagents and con-
ditions: (i) 6 M HCl, then propylene oxide, EtOH, 3a: 50%; (ii) 6 M HCl, then DOWEX
50WX8, 3c: 63%; (iii) HCl, MeOH, then (t-BuOCO)2O, DMAP, MeCN, 4a: 83%; 4b: 62%;
4c: 66%; 4d: 87%; (iv) BH3–THF, 5a: 94%; 5b: 69%; 5c: 51%; (v) 1 M HCl, then DOWEX
50WX8, 6a: 90%; 6b: 70%; 6c: 78%.

130
M. Oba et al. / Tetrahedron 65 (2009) 128–133
produce (2S,3R)-2-carboxypyrrolidine-3-acetic acid (8, CPAA), an
NMDA receptor agonist,21 in 53% yield (3 steps) based on the
pyroglutamate 4d.
for 10 min. A solution of the olefin 1 (1.56 g, 5.01 mmol) in ether
(40 mL) was added to the resulting solution at ꢀ80 ꢁC. After 4 h,
saturated aqueous NH4Cl was added and the reaction mixture was
warmed to room temperature. The organic layer was separated,
dried over MgSO4 and concentrated in vacuo. The residue was
chromatographed on silica gel (hexanes/ethyl acetate¼50:50) to
yield the title compound 2a (1.48 g, 90%) as colourless crystals, mp
As an extension of the present protocol to the preparation of 3-
substituted
g-aminobutyric acid (GABA) derivatives, we have
demonstrated here a formal total synthesis of (R)-baclofen, which is
known as a muscle relaxer and an antispastic agent.22 Although
baclofen has been commercialized in its racemic form, its biological
activity resides exclusively in the (R)-enantiomer.23 Many chemical
syntheses of baclofen have already been described.24–30 As outlined
in Scheme 3, after methanolysis of the ABO function of 2c, in-
stallation of benzyl protective group into the lactam nitrogen fol-
lowed by LiOH-promoted hydrolysis of the methyl ester yielded
pyroglutamic acid 11, which was spectroscopically identical to that
previously reported.31,32 The acid 11 can be converted to baclofen as
described by Chang and co-workers.31,32
130–132 ꢁC. 1H NMR (CDCl3):
d
¼1.12 and 1.13 (2d, J¼7 Hz, 3H), 1.34
and 1.35 (2s, 3H), 1.43–1.48 (m, 1H), 1.51 (s, 9H), 1.94 (d, J¼17 Hz,
1H), 2.04 (m, 1H), 2.52 (m, 1H), 3.00 (m, 1H), 3.46 (m, 1H), 3.88 (m,
1H), 3.96–4.11 (m, 3H) ppm. 13C NMR (CDCl3):
d
¼21.29 and 21.43,
21.78, 26.89 and 27.37, 27.79 and 27.83, 33.73 and 33.77, 40.15,
59.32 and 59.40, 65.48 and 65.91, 73.54 and 73.77, 78.97 and
79.07, 82.51, 119.98 and 120.09, 150.21 and 150.29, 174.93 ppm.
HRMS (EI, 30 eV): m/z 327.1642 (Mþ, calcd for C16H25NO6
327.1682).
4.1.2. (4R,5S)-1-tert-Butoxycarbonyl-4-phenyl-5-(5-methyl-2,7,8-
trioxabicyclo[3.2.1]oct-1-yl)-2-pyrrolidone (2b)
Cl
Cl
A
solution of phenylmagnesium bromide, prepared from
bromobenzene (5.30 g, 33.8 mmol) and magnesium (822 mg,
33.8 mmol) in ether (50 mL), was added to a stirred suspension of
CuBr–SMe2 (3.47 g, 16.9 mmol) in ether (50 mL) at ꢀ40 ꢁC under an
argon atmosphere, and the mixture was stirred for 30 min. A solu-
tion of the olefin 1 (1.05 g, 3.37 mmol) and chlorotrimethylsilane
(1.17 g, 10.8 mmol) in ether (50 mL) was added to the resulting so-
lution at ꢀ80 ꢁC. After 1 h, saturated aqueous NH4Cl was added and
the reaction mixture was warmed to room temperature. The organic
layer was separated, dried over MgSO4 and concentrated in vacuo.
The residue was chromatographed on silica gel (hexanes/ethyl
acetate¼50:50) to yield the title compound 2b (933 mg, 71%) as
i
ii
2c
CO2Me
CO2Me
O
O
N
H
N
Bn
9
10
Cl
Cl
ref 31,32
iii
CO2H
O
HO2C
(R)-baclofen
NH2
N
a pale yellow oil. 1H NMR (CDCl3):
d¼1.35 and 1.37 (2s, 3H), 1.48 (m,
Bn
1H),1.48 (s, 9H), 2.07 (m,1H), 2.43 (m,1H), 3.27 (m,1H), 3.50 (m,1H),
3.63 (m, 1H), 3.92 (m, 1H), 4.03 (m, 1H), 4.11 (m, 1H), 4.42 and 4.46
11
Scheme 3. Formal total synthesis of (R)-baclofen. Reagents and conditions: (i) HCl,
MeOH, 75%; (ii) PhCH2Br, NaH, THF, 55%; (iii) 1 M LiOH, THF, 98%.
(2s,1H), 7.17–7.32 (m, 5H) ppm.13C NMR (CDCl3):
d
¼21.78, 27.73 and
27.78, 33.71 and 33.76, 37.11 and 37.59, 39.56 and 39.60, 59.42 and
59.51, 65.54 and 65.96, 73.58 and 73.87, 79.10 and 79.28, 82.67,
119.85 and 119.98, 126.17, 126.94, 128.93, 143.92 and 143.98, 149.67
and 149.75, 174.62 ppm. HRMS (EI, 70 eV): m/z 390.1951 [(MþH)þ,
calcd for C21H28NO6 390.1917].
3. Conclusion
We have developed a simple method for the stereoselective
preparation of 3-substituted glutamic acids and prolines using
Michael addition to the unsaturated pyroglutamic ABO ester 1
where it was not necessary to change the oxidation state of the
carboxyl function. The utility of the present protocol is demon-
strated by the concise synthesis of some biologically active non-
proteinogenic amino acids such as chlorpheg and CPAA. As an
application of this methodology, a formal total synthesis of baclofen
was also demonstrated.
4.1.3. (4R,5S)-1-tert-Butoxycarbonyl-4-(4-chlorophenyl)-5-(5-
methyl-2,7,8-trioxabicyclo[3.2.1]oct-1-yl)-2-pyrrolidone (2c)
A solution of 4-chlorophenylmagnesium bromide, prepared
from 4-bromochlorobenzene (15.3 g, 79.9 mmol) and magnesium
(1.95 g, 80.2 mmol) in ether (80 mL), was added to a stirred sus-
pension of CuBr–SMe2 (8.22 g, 40.0 mmol) in ether (80 mL) at
ꢀ40 ꢁC under an argon atmosphere, and the mixture was stirred
for 30 min. A solution of the olefin 1 (2.49 g, 8.00 mmol) and
chlorotrimethylsilane (2.76 g, 25.4 mmol) in ether (80 mL) was
added to the resulting solution at ꢀ80 ꢁC. After 1 h, saturated
aqueous NH4Cl was added and the reaction mixture was warmed
to room temperature. The organic layer was separated, dried over
MgSO4 and concentrated in vacuo. The residue was chromato-
graphed on silica gel (hexanes/ethyl acetate¼50:50) to yield the
title compound 2c (2.30 g, 68%) as a pale yellow oil. 1H NMR
4. Experimental
4.1. General
Melting points are uncorrected. 1H and 13C NMR spectra were
measured at 400 and 100 MHz, respectively. All chemical shifts are
reported as d values (ppm) relative to residual chloroform (dH 7.26),
HDO (dH 4.65) or the central peak of deuteriochloroform (dC 77.0).
High-resolution mass spectra (HRMS) were determined using
perfluorokerosene as an internal standard. Optical rotations were
measured on a HORIBA SEPA-200 polarimeter. Solvents and re-
agents were of commercial grade and purified if necessary.
(CDCl3):
d
¼1.36 and 1.38 (2s, 3H), 1.49 (m, 1H), 1.49 (s, 9H), 2.08 (m,
1H), 2.40 (m, 1H), 3.28 (m, 1H), 3.51 (m, 1H), 3.61 (m, 1H), 3.93 (m,
1H), 4.04 (m, 1H), 4.11 (m, 1H), 4.35 and 4.39 (2s, 1H), 7.12 and 7.13
(2d, J¼8 Hz, 2H), 7.28 and 7.29 (2d, J¼8 Hz, 2H) ppm. 13C NMR
(CDCl3):
d
¼21.80, 27.75 and 27.80, 33.72 and 33.78, 36.62 and 37.11,
4.1.1. (4S,5S)-1-tert-Butoxycarbonyl-4-methyl-5-(5-methyl-2,7,8-
trioxabicyclo[3.2.1]oct-1-yl)-2-pyrrolidone (2a)
MeLi in ether (1.20 M, 25.0 mL, 30.0 mmol) was added to
a stirred suspension of CuI (2.86 g, 15.0 mmol) in ether (40 mL) at
ꢀ15 ꢁC under an argon atmosphere, and the mixture was stirred
39.32 and 39.36, 59.47 and 59.57, 65.55 and 65.96, 73.63 and 73.91,
79.21 and 79.37, 82.90, 119.74 and 119.87, 127.62, 129.08, 132.79
and 132.81, 142.35 and 142.41, 149.59 and 149.67, 174.24 ppm.
HRMS (EI, 70 eV): m/z 423.1485 (Mþ, calcd for C21H26NO6Cl
423.1449).

M. Oba et al. / Tetrahedron 65 (2009) 128–133
131
4.1.4. (4R,5S)-1-tert-Butoxycarbonyl-4-(bis(ethoxycarbonyl)meth-
yl)-5-(5-methyl-2,7,8-trioxabicyclo[3.2.1]oct-1-yl)-2-pyrrolidone
(2d)
in acetonitrile (5 mL) at room temperature for 1.5 h. After removal
of the solvent, the residue was extracted with ethyl acetate. The
organic layer was washed successively with aqueous KHSO4 and
brine, dried over MgSO4 and concentrated. The residue was chro-
matographed on silica gel (hexanes/ethyl acetate¼50:50) to yield
the title compound 4a (761 mg, 83%, 2 steps) as a pale yellow oil. 1H
Diethyl malonate (4.80 g, 30.0 mmol) was added dropwise to
a stirred suspension of sodium hydride (60% dispersion in mineral
oil, 1.20 g, 30.0 mmol) in THF (40 mL) at 0 ꢁC under an argon at-
mosphere, and the mixture was stirred for 30 min. A solution of the
olefin 1 (1.87 g, 6.01 mmol) and Me3SiCl (1.30 g, 12.0 mmol) in THF
(40 mL) was added to the resulting mixture and the reaction mix-
ture was stirred at room temperature overnight. The reaction was
quenched with saturated aqueous NH4Cl and the organic layer was
separated, dried over MgSO4 and concentrated in vacuo. The residue
was chromatographed on silica gel (hexanes/ethyl acetate¼50:50)
to produce quantitative yield of the title compound 2d (2.83 g) as
NMR (CDCl3):
d
¼1.23 (d, J¼7 Hz, 3H), 1.47 (s, 9H), 2.14 (dd, J¼17 and
5 Hz, 1H), 2.36 (m, 1H), 2.77 (dd, J¼17 and 8 Hz, 1H), 3.76 (s, 3H),
4.17 (d, J¼4 Hz, 1H) ppm. 13C NMR (CDCl3):
¼20.37, 27.80, 29.62,
d
39.39, 52.46, 65.87, 83.60, 149.29, 171.36, 172.73 ppm. HRMS (EI,
70 eV): m/z 258.1359 [(MþH)þ, calcd for C12H19NO5 258.1341].
4.1.8. Methyl (2S,3R)-N-tert-butoxycarbonyl-3-
phenylpyroglutamate (4b)
a colourless oil. 1H NMR (CDCl3):
d
¼1.247 and 1.249 (2t, J¼7 Hz, 3H),
According to the procedure described for the synthesis of com-
pound 4a, methanolysis of the compound 2b (738 mg, 1.90 mmol)
with hydrogen chloride in methanol (50 mL) followed by protection
with di-tert-butyl dicarbonate (497 mg, 2.28 mmol) and DMAP
(232 mg, 1.90 mmol) in acetonitrile (20 mL) yielded the title com-
pound 4b (378 mg, 62%, 2 steps) as a pale yellowoil.1H NMR (CDCl3):
1.26 (t, J¼7 Hz, 3H), 1.33 and 1.34 (2s, 3H), 1.42–1.47 (m, 1H), 1.50 (s,
9H), 2.04 (m,1H), 2.32 (m,1H), 3.03–3.18 (m, 2H), 3.45–3.49 (m, 2H),
3.88 (m, 1H), 3.99 (m, 1H), 4.06 (m, 1H), 4.18 (m, 4H), 4.38 and 4.43
(2s, 1H) ppm. 13C NMR (CDCl3):
d¼13.93, 13.97, 21.77, 27.77 and
27.80, 32.07 and 32.54, 33.71 and 33.74, 36.49, 55.10 and 55.15,
59.44 and 59.52, 61.32, 61.35, 61.82, 73.64 and 73.92, 79.12 and
79.33, 82.59, 119.75 and 119.88, 149.46 and 149.53, 167.59, 167.61,
173.63 ppm. HRMS (EI, 70 eV): m/z 471.2134 (Mþ, calcd for
C22H33NO10 471.2104).
d
¼1.48 (s, 9H), 2.69 (dd, J¼17 and 5 Hz, 1H), 3.07 (dd, J¼17 and 9 Hz,
1H), 3.46 (ddd, J¼17, 5 and 4 Hz,1H), 3.80 (s, 3H), 4.56 (d, J¼4 Hz,1H),
7.23–7.40 (m, 5H) ppm. 13C NMR (CDCl3):
d
¼27.82, 38.82, 39.68,
52.65, 66.24, 83.93, 126.47, 127.85, 129.21, 141.03, 149.05, 171.15,
172.40 ppm. HRMS (EI, 70 eV): m/z 319.1440 (Mþ, calcd for
C17H21NO5 319.1420).
4.1.5. (2S,3S)-3-Methylglutamic acid (3a)13,33
A mixture of compound 2a (1.47 g, 4.49 mmol) and 6 M HCl
(10 mL) was heated to reflux overnight. The cooled solution was
washed with chloroform and concentrated to dryness. The residue
was then dissolved in a mixture of propylene oxide (4 mL) and
ethanol (12 mL) and the solution was refluxed for 1 h. The pre-
cipitated solids were collected by filtration to yield the title com-
4.1.9. Methyl (2S,3R)-N-tert-butoxycarbonyl-3-(4-
chlorophenyl)pyroglutamate (4c)
According to the procedure described for the synthesis of com-
pound 4a, methanolysis of the compound 2c (1.28 g, 3.02 mmol)
with hydrogen chloride in methanol (60 mL) followed by protection
with di-tert-butyl dicarbonate (793 mg, 3.63 mmol) and DMAP
(370 mg, 3.03 mmol) in acetonitrile (20 mL) yielded the title com-
pound 4c (703 mg, 66%, 2 steps) as a pale yellowoil.1H NMR (CDCl3):
pound 3a (362 mg, 50%) as colourless crystals, mp 177–178 ꢁC (lit.
23
mp 182–184 ꢁC13; mp 171–173 ꢁC33). [
a
]
D
þ41.0 (c 1.00, 6 M HCl)
20
25
(lit. [
a
]
D
þ41.9 (c 0.82, 6 M HCl)13; [
a
]
þ42.0 (c 0.9, 6 M HCl)33). 1H
D
NMR (NaOD–D2O):
d
¼0.76 (d, J¼7 Hz, 3H), 1.77 (dd, J¼13 and 11 Hz,
d
¼1.48 (s, 9H), 2.63 (dd, J¼17 and 5 Hz,1H), 3.06 (dd, J¼17 and 9 Hz,
1H), 1.91 (m, 1H), 2.22 (dd, J¼13 and 3 Hz, 1H), 2.89 (d, J¼6 Hz,
1H), 3.44 (ddd, J¼9, 5 and 4 Hz,1H), 3.80 (s, 3H), 4.51 (d, J¼4 Hz,1H),
1H) ppm.
7.17 (d, J¼9 Hz, 2H), 7.34 (d, J¼9 Hz, 2H) ppm. 13C NMR (CDCl3):
d
¼27.83, 38.72, 39.18, 52.75, 66.10, 84.13, 127.90, 129.40, 133.81,
4.1.6. (2S,3R)-3-(4-Chlorophenyl)glutamic acid (chlorpheg) (3c)16
A mixture of compound 2c (552 mg, 1.30 mmol) and 6 M HCl
(10 mL) was heated to reflux overnight. The cooled solution was
washed with chloroform and concentrated to dryness. The residue
was submitted to ion-exchange column chromatography on
DOWEX 50WX8 and elution with 1 M NH4OH to yield the ammo-
nium salt of compound 3c. The salt was then dissolved in water and
the solution was acidified to pH 3 with 1 M HCl. The precipitated
solids were collected by filtration to yield the title compound 3c
(210 mg, 63%) as colourless crystals, mp 188–190 ꢁC (lit.16 mp
139.40, 148.99, 170.91, 171.97 ppm. HRMS (EI, 70 eV): m/z 353.1059
(Mþ, calcd for C17H20NO5Cl 353.1030).
4.1.10. Methyl (2S,3R)-N-tert-butoxycarbonyl-3-
(bis(ethoxycarbonyl)methyl)pyroglutamate (4d)
According to the procedure described for the synthesis of
compound 4a, methanolysis of the compound 2d (9.18 g,
19.5 mmol) with hydrogen chloride in methanol (200 mL) followed
by protection with di-tert-butyl dicarbonate (4.58 g, 21.0 mmol)
and DMAP (2.44 g, 20.0 mmol) in acetonitrile (30 mL) yielded the
title compound 4d (6.79 g, 87%, 2 steps) as a colourless oil. 1H NMR
24
20
194.7–194.9 ꢁC). [
a]
þ21.0 (c 0.10, 1 M NaOH) (lit.16
[a
]
þ21.5 (c
D
D
0.39, 1 M NaOH)). 1H NMR (NaOD–D2O):
12 Hz,1H), 2.54 (dd, J¼15 and 4 Hz,1H), 3.07 (ddd, J¼12, 7 and 4 Hz,
1H), 3.18 (d, J¼7 Hz, 1H), 7.07 (d, J¼8 Hz, 2H), 7.17 (d, J¼8 Hz,
2H) ppm.
d
¼2.41 (dd, J¼15 and
(CDCl3):
d
¼1.27 (t, J¼7 Hz, 3H), 1.28 (t, J¼7 Hz, 3H), 1.48 (s, 9H), 2.48
(dd, J¼17 and 3 Hz,1H), 2.85–2.98 (m, 2H), 3.54 (d, J¼7 Hz,1H), 3.79
(s, 3H), 4.23 (m, 4H), 4.54 (d, J¼3 Hz, 1H) ppm. 13C NMR (CDCl3):
d
¼13.92, 13.94, 27.84, 33.61, 35.50, 52.78, 54.42, 61.71, 62.20, 62.26,
83.97, 149.02, 167.08, 167.15, 170.91, 171.45 ppm. HRMS (EI, 70 eV):
4.1.7. Methyl (2S,3S)-N-tert-butoxycarbonyl-3-
methylpyroglutamate (4a)
m/z 402.1740 [(MþH)þ, calcd for C18H28NO9 402.1764].
A solution of compound 2a (1.17 g, 3.57 mmol) in methanol
(60 mL) was cooled in an ice bath and a slow stream of HCl was
introduced with stirring to saturation. After being stirred at room
temperature for 3 h, the solution was concentrated and the residue
was extracted with ethyl acetate. The organic layer was washed
with saturated aqueous NaHCO3, dried over MgSO4 and concen-
trated to yield crude methyl 3-methylpyroglutamate (550 mg, 98%).
The obtained pyroglutamate was treated with di-tert-butyl
dicarbonate (915 mg, 4.19 mmol) and DMAP (427 mg, 3.50 mmol)
4.1.11. Methyl (2S,3S)-N-tert-butoxycarbonyl-3-
methylprolinate (5a)
A solution of borane in THF (1 M, 9 mL, 9 mmol) was added to
a solution of compound 4a (761 mg, 2.96 mmol) in THF (3 mL)
under an argon atmosphere, and the mixture was stirred at room
temperature overnight. The reaction was quenched by addition of
methanol, and after being stirred for 1 h, the mixture was diluted
with dichloromethane. The organic layer was then dried over
MgSO4 and concentrated. The crude product was purified by flash

132
M. Oba et al. / Tetrahedron 65 (2009) 128–133
column
chromatography
on
silica
gel
(hexanes/ethyl
1.02 mmol) in refluxing 1 M HCl (15 mL) followed by ion exchange
chromatography on DOWEX 50WX8 produced the title compound
acetate¼50:50) to produce the title compound 5a (678 mg, 94%) as
21
a colourless oil. 1H NMR (CDCl3):
d
¼1.13 and 1.14 (2d, J¼7 Hz, 3H),
6c (179 mg, 78%) as colourless crystals, mp 240–242 ꢁC. [
(c 0.1, H2O). 1H NMR (D2O):
¼2.03 (m, 1H), 2.31 (m, 1H), 3.32 (m,
a]
þ68.0
D
1.38 and 1.44 (2s, 9H), 1.51 (m, 1H), 2.02 (m, 1H), 2.29 (m, 1H), 3.40–
d
3.61 (m, 2H), 3.71 and 3.72 (2s, 3H), 3.73 and 3.84 (2d, J¼6 Hz,
2H), 3.44 (m, 1H), 3.90 (d, J¼9 Hz, 1H), 7.19 (d, J¼9 Hz, 2H), 7.26 (d,
1H) ppm. 13C NMR (CDCl3):
d
¼18.23 and 18.44, 28.22 and 28.35,
J¼9 Hz, 2H) ppm. 13C NMR (D2O):
¼33.05, 45.96, 47.33, 64.58,
d
32.08 and 32.48, 38.36 and 39.49, 45.68 and 45.84, 51.83 and 52.02,
65.62 and 66.12, 79.72 and 79.82, 153.71 and 154.37, 173.22 and
173.45 ppm. HRMS (EI, 70 eV): m/z 243.1501 (Mþ, calcd for
C12H21NO4 243.1471).
129.04, 129.20, 133.07, 136.77, 170.51 ppm. HRMS (EI, 70 eV): m/z
225.0582 (Mþ, calcd for C11H12NO2Cl 225.0557).
4.1.17. (2S,3R)-3-Carboxymethylproline (8)35
A solution of DIBAL-H in toluene (1 M, 5.00 mL, 5.00 mmol) was
added to a solution of the pyroglutamate 4d (674 mg, 1.68 mmol) in
THF (10 mL) at ꢀ80 ꢁC under an argon atmosphere, and the reaction
mixture was stirred for 1 h. Then, the mixture was quenched with
methanol and warmed up to room temperature. After addition of
saturated aqueous potassium tartarate (17 mL) and ethyl acetate
(17 mL), the mixture was stirred for an additional 15 min. The or-
ganic layer was washed with brine, dried over MgSO4 and con-
centrated, and the residue was dissolved in dichloromethane
(10 mL). Et3SiH (390 mg, 3.35 mmol) and boron trifluoride diethyl
etherate (477 mg, 3.36 mmol) were added to the solution at 0 ꢁC
under an argon atmosphere, and the resulting solution was stirred
for 2 h. Then the reaction mixture was quenched with saturated
aqueous NaHCO3 and the organic layer was dried over MgSO4 and
concentrated to produce crude methyl (2S,3R)-3-(bis(ethoxy-
carbonyl)methyl)prolinate (7). Although the obtained prolinate 7
could be used in the next step without further purification, a small
aliquot obtained from a separate run was purified by column
chromatography on silica gel (chloroform/ethanol¼85:15) for the
4.1.12. Methyl (2S,3R)-N-tert-butoxycarbonyl-3-
phenylprolinate (5b)
According to the procedure described for the synthesis of
compound 5a, treatment of the compound 4b (378 mg, 1.18 mmol)
in THF (10 mL) with an 1 M solution of borane in THF (3.6 mL,
3.6 mmol) yielded the title compound 5b (248 mg, 69%) as a col-
ourless oil. 1H NMR (CDCl3):
d
¼1.41 and 1.48 (2s, 9H), 2.03 (m, 1H),
2.30 (m, 1H), 3.44 (m, 1H), 3.61 and 3.76 (2m, 2H), 3.70 and 3.71 (2s,
3H), 4.24 and 4.38 (2d, J¼7 Hz,1H), 7.22–7.36 (m, 5H) ppm. 13C NMR
(CDCl3):
d
¼28.23 and 28.39, 32.24 and 32.96, 45.95 and 46.11, 48.71
and 49.91, 51.95 and 52.17, 65.09 and 65.78, 80.08 and 80.19, 126.88
and 126.93, 127.11 and 127.24, 128.72 and 128.75, 140.50 and
140.86, 153.58 and 154.22, 173.05 and 173.19 ppm. HRMS (EI,
70 eV): m/z 305.1675 (Mþ, calcd for C17H23NO4 305.1627).
4.1.13. Methyl (2S,3R)-N-tert-butoxycarbonyl-3-(4-
chlorophenyl)prolinate (5c)
According to the procedure described for the synthesis of
compound 5a, treatment of the compound 4c (703 mg, 1.99 mmol)
in THF (15 mL) with an 1 M solution of borane in THF (6.0 mL,
6.0 mmol) yielded the title compound 5c (345 mg, 51%) as a col-
structural elucidation. 1H NMR (CDCl3):
d¼1.251 (t, J¼7 Hz, 3H),
1.254 (t, J¼7 Hz, 3H), 1.62 (m, 1H), 2.06 (m, 1H), 2.20 (br s, 1H), 2.90
(m, 1H), 3.00 (m, 2H), 3.51 (d, J¼9 Hz, 1H), 3.68 (d, J¼6 Hz, 1H), 3.71
ourless oil. 1H NMR (CDCl3):
2.30 (m, 1H), 3.40 (m, 1H), 3.60 and 3.74 (2m, 2H), 3.70 and 3.71 (2s,
d
¼1.41 and 1.48 (2s, 9H), 1.98 (m, 1H),
(s, 3H), 4.18 (m, 4H) ppm. 13C NMR (CDCl3):
42.61, 46.16, 52.20, 54.93, 61.46, 61.53, 63.05, 168.19, 168.36,
174.62 ppm. HRMS (EI, 70 eV): m/z 287.1383 (Mþ, calcd for
C13H21NO6 287.1369).
d
¼13.96, 14.02, 30.48,
3H), 4.19 and 4.32 (2d, J¼7 Hz, 1H), 7.16 (d, J¼9 Hz, 2H), 7.30 (d,
J¼9 Hz, 2H) ppm. 13C NMR (CDCl3):
¼28.22 and 28.38, 32.25 and
d
32.98, 45.89 and 46.04, 48.13 and 49.32, 52.04 and 52.26, 65.04 and
65.70, 80.23 and 80.34, 128.28 and 128.34, 128.88 and 128.92,
132.91 and 133.04,138.92 and 139.29,153.50 and 154.19,172.79 and
172.96 ppm. HRMS (EI, 70 eV): m/z 339.1196 (Mþ, calcd for
C17H22NO4Cl 339.1237).
Deprotection of the crude prolinate 7 was carried out in refluxing
1 M HCl (18 mL) overnight. The cooled solution was washed with
chloroform and concentrated to dryness. The residue was submitted
to ion-exchange column chromatography on DOWEX 50WX8 and
elution with 1 M NH4OH to produce the ammonium salt of the title
compound. Thesaltwasthen dissolvedinwaterandthe solutionwas
acidified to pH 3 with 1 M HCl. The precipitated solids werecollected
by filtration and recrystallized from water/acetone to yield the title
compound 8 (153 mg, 53%, 3 steps) as colourless crystals, mp 236–
4.1.14. (2S,3S)-3-Methylproline (6a)34
A mixture of compound 5a (276 mg, 1.13 mmol) and 1 M HCl
(20 mL) was heated to reflux for 3 h. The cooled solution was
washed with chloroform and concentrated to dryness. The residue
was submitted to ion-exchange column chromatography on
DOWEX 50WX8 and elution with 1 M NH4OH to yield the title
compound 6a (132 mg, 90%) as colourless crystals, mp 240–242 ꢁC
22
25
239 ꢁC (lit.35 mp 242–244 ꢁC). [
a
]
þ19.0 (c 0.5, H2O) (lit.35
[a]
D
D
þ20.0 (c 0.1, H2O)). 1H NMR (D2O):
¼1.64 (m,1H), 2.15 (m,1H), 2.39
d
(dd, J¼16 and 9 Hz, 1H), 2.55 (m, 1H), 2.68 (dd, J¼16 and 5 Hz, 1H),
3.27 (m, 2H), 3.65 (d, J¼8 Hz, 1H) ppm.
22
20
(lit.34 mp 245 ꢁC). [
a
]
ꢀ28.0 (c 1.00, H2O) (lit.34
[
a
]
ꢀ30.0 (c 0.27,
D
D
H2O)). 1H NMR (D2O):
d
¼1.06 (d, J¼7 Hz, 3H), 1.51 (m, 1H), 2.03 (m,
4.1.18. Methyl (2S,3R)-3-(4-chlorophenyl)pyroglutamate (9)
1H), 2.22 (m, 1H), 3.21 (m, 2H), 3.43 (d, J¼8 Hz, 1H) ppm.
A solution of compound 2c (4.99 g, 11.8 mmol) in methanol
(200 mL) was cooled in an ice bath, and a slow stream of HCl was
introduced with stirring to saturation. After being stirred at room
temperature for 3 h, the solution was concentrated and the resi-
due was extracted with ethyl acetate. The organic layer was
washed with saturated aqueous NaHCO3, dried over MgSO4 and
concentrated. The residue was chromatographed on silica gel and
elution with ethyl acetate yielded the title compound 9 as a col-
4.1.15. (2S,3R)-3-Phenylproline (6b)34
According to the procedure described for the synthesis of
compound 6a, deprotection of the compound 5b (248 mg,
0.812 mmol) in refluxing 1 M HCl (15 mL) followed by ion exchange
chromatography on DOWEX 50WX8 produced the title compound
6b (108 mg, 70%) as colourless crystals, mp 247–249 ꢁC (lit.34 mp
25
20
>250 ꢁC). [
a]
þ65.0 (c 0.2, H2O) (lit.34
[
a
]
þ65.0 (c 0.2,1 M HCl)).
ourless oil (2.24 g, 75%). 1H NMR (CDCl3):
d
¼2.48 (dd, J¼17 and
D
D
1H NMR (D2O):
3.44 (m, 1H), 3.94 (d, J¼9 Hz, 1H), 7.17–7.29 (m, 5H) ppm.
d
¼2.05 (m, 1H), 2.31 (m, 1H), 3.29–3.38 (m, 2H),
7 Hz, 1H), 2.86 (dd, J¼17 and 9 Hz, 1H), 3.72 (ddd, J¼9, 7 and 5 Hz,
1H), 3.77 (s, 3H), 4.20 (d, J¼5 Hz, 1H), 6.08 (br s, 1H), 7.23 (d,
J¼8 Hz, 2H), 7.34 (d, J¼8 Hz, 2H) ppm. 13C NMR (CDCl3):
¼37.71,
d
4.1.16. (2S,3R)-3-(4-Chlorophenyl)proline (6c)
According to the procedure described for the synthesis of
compound 6a, deprotection of the compound 5c (345 mg,
43.17, 52.78, 62.61, 128.23, 129.19, 133.42, 140.18, 171.50,
176.38 ppm. HRMS (EI, 70 eV): m/z 253.0503 (Mþ, calcd for
C12H12NO3Cl 253.0506).

M. Oba et al. / Tetrahedron 65 (2009) 128–133
133
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Sodium hydride (60% dispersion in mineral oil, 48.0 mg,
2.00 mmol) was added to a solution of 9 (253 mg, 0.997 mmol) and
benzyl bromide(205 mg,1.20 mmol)inTHF (10 mL)and thereaction
mixture was refluxed for 1 h. After cooling, the mixture was diluted
with ether and washed successively with saturated aqueous NH4Cl
and water. The organic layer was dried overMgSO4 and concentrated
in vacuo. The residue was chromatographed on silica gel, and elution
with a mixture of hexane and ethyl acetate (70:30) yielded the title
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9. Blaskovich, M. A.; Lajoie, G. A. J. Am. Chem. Soc. 1993, 115, 5021–5030.
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´
11. Hansen, D. B.; Wan, X.; Carroll, P. J.; Joullie, M. M. J. Org. Chem. 2005, 70, 3120–
(ddd, J¼9, 4 and 3 Hz, 1H), 3.69 (s, 3H), 3.88 (d, J¼3 Hz, 1H), 4.03 (d,
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2H), 7.21 (d, J¼8 Hz, 2H), 7.27–7.31 (m, 3H) ppm. 13C NMR (CDCl3):
3126.
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¼37.76, 40.51, 45.81, 52.59, 66.13, 127.75, 127.99, 128.68, 128.73,
129.08,133.30,135.25,140.70,171.24,173.64 ppm. HRMS (EI, 70 eV):
m/z 343.0963 (Mþ, calcd for C19H18NO3Cl 343.0975).
4.1.20. (2S,3R)-N-Benzyl-3-(4-chlorophenyl)pyroglutamic
acid (11)31,32
LiOH (1 M, 9 mL) was added to a solution of 10 (441 mg,
1.28 mmol) in THF (15 mL), and the reaction mixture was stirred for
2 h. After removal of the solvent, the residue was diluted with
water and washed with ether. The aqueous layer was then acidified
to pH 3 with 1 M HCl. The precipitated solids were collected by
filtration to yield the title compound 11 (411 mg, 98%) as colourless
crystals, mp 155–158 ꢁC (lit.31,32 mp 168–169 ꢁC). The structure was
also confirmed by comparison of their spectral data with those
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reported in the literature.31,32 1H NMR (CDCl3):
d
¼2.56 (dd, J¼17
and 4 Hz, 1H), 3.08 (dd, J¼17 and 10 Hz, 1H), 3.59 (ddd, J¼10, 4, and
3 Hz, 1H), 3.92 (d, J¼3 Hz, 1H), 3.99 (d, J¼15 Hz, 1H), 5.21 (d,
J¼15 Hz,1H), 6.98 (d, J¼8 Hz, 2H), 7.19–7.23 (m, 2H), 7.22 (d, J¼8 Hz,
2H), 7.27–7.30 (m, 3H) ppm.
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